Familial Dysautonomia (FD) is a rare genetic disease characterized by severe and progressive sympathetic and sensory neuron loss caused by a highly conserved germline point mutation of the human Elp1 (IKBKAP) gene. Elp1 is a highly conserved subunit of the hetero-hexameric transcriptional Elongator complex, but how it functions in disease vulnerable neurons is very poorly understood. We propose to study the role of Elp1 in sympathetic neuron development and innervation. The project is outlined in three specific aims to: (1) characterize Elp1 function in sympathetic neuron target tissue innervation and in maintaining adult sympathetic neuron innervation homeostasis, (2) to identify signaling pathways and interacting proteins that mediate its function in the neuron cytoplasm and (3) to characterize its role in nerve growth factor signaling which is essential for their normal survival and target tissue innervation. Millions of humans are afflicted with diseases involving sympathetic and sensory neurons, yet almost all of them are untreatable because the mechanisms regulating their growth and differentiation are very poorly understood. We anticipate that these studies focused on a rare neuropathy-associated protein will identify new signal transduction pathways that are essential for peripheral neuron survival, differentiation and innervation homeostasis. Moreover, we anticipate that these studies will elucidate essential disease-relevant signaling pathways in sympathetic neurons that may be exploited to treat developmental and degenerative peripheral neuropathies.